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An Intron Control Region Differentially Regulates Expression of Thyroid Hormone Receptor ß2 in the Cochlea, Pituitary, and Cone Photoreceptors

Department of Human Genetics (I.J.), Mount Sinai School of Medicine, New York, New York 10029; and National Institutes of Health (L.N., H.L., D.F.), National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Endocrinology Branch, Bethesda, Maryland 20892-1772

Address all correspondence and requests for reprints to: Douglas Forrest, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Endocrinology Branch, 10 Center Drive, Bethesda, Maryland 20892-1772. E-mail: forrestd{at}niddk.nih.gov.

The Thrb gene, encoding thyroid hormone receptor ß (TRß), serves key roles in endocrine regulation and the development of the senses of hearing and color vision. The versatile functions of this gene depend upon its expression of distinct receptor isoforms by differential promoter activation. The TRß2 isoform has a particularly specialized distribution including in the anterior pituitary and cochlea. TRß2 is also found in immature cone photoreceptors where it has a unique role in programming the expression pattern of opsin photopigments that mediate color vision. Given the importance of precise, tissue-specific expression for the function of TRß2, we investigated the genomic control elements that direct this expression in vivo using lacZ reporter transgenes in mice. The TRß2 promoter region is sufficient for cochlear expression, whereas a complex intron control region is necessary for pituitary and retinal expression. In the retina, the intron region directs peak expression in the embryo in postmitotic, immature cones. The retinal control region is further subdivided into domains that specify and amplify expression, respectively, indicating that timely, cone-specific expression reflects an integrated response to complex signals. The mammalian Thrb gene has therefore incorporated several mechanisms into a multifunctional intron control region that regulates developmental induction of the distant promoter. This specialized genomic organization underlies the unique expression pattern and functions of TRß2.

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Nuclear Receptors:   TRβ

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